solution was prepared by dissolving sodium hydroxide (37.0
kg, 925 mol) in water (250 L). The reaction mixture
obtained above was added dropwise to this aqueous solution
with stirring at 25-30 °C. After completion of the addition,
the resulting mixture was further stirred at ambient temper-
ature for 15 min, the aqueous layer was separated, and the
organic layer was re-extracted by water (25 L). The aqueous
layers were combined, and to this solution were added ethyl
acetate (625 L), acetone (125 L), and 35% hydrochloric acid
in water (37.5 L) with stirring at 18-25 °C. The layers were
separated, and the aqueous layer was re-extracted with ethyl
acetate (150 L). The combined organic layer was washed
with saturated sodium hydrogen carbonate in water (50 L),
concentrated to ∼125 L under reduced pressure, treated with
2-propanol (125 L), and again concentrated to 125 L under
ambient conditions. To the residue was added water (375
L), the mixture was cooled to 5 °C, and the precipitate was
filtered off, washed with water (50 L), and dried under
reduced pressure to afford 2 (38.0 kg, 96% yield) as a
The final refinement converged to R ) 0.036 and Rw )
0.038.
Large-Scale Preparation of 4′-Acetyl-2′-bromomethane-
sulfonanilide (3) (Method C). Bromine (31.0 kg, 194 mol)
was added dropwise over 1 h to a solution of 4′-acetyl-
methanesulfonanilide (2) (39.4 kg, 185 mol) and sodium
acetate (75.8 kg, 924 mol) in glacial acetic acid (788 L) and
water (263 L) with stirring at 15 °C. After completion of
the addition, the resulting mixture was further stirred at the
same temperature for 2 h and was then concentrated under
reduced pressure to ∼260 L. To the residue was added water
(591 L), and stirring was continued at 5 °C overnight. The
precipitate was filtered off and washed with water (150 L).
Drying under reduced pressure afforded 4′-acetyl-2′-bro-
momethanesulfonanilide (3) (52.4 kg, 97% yield) as a white
solid, identical with the material obtained in the preceding
experiment (1H NMR, TLC).
4′-(2-Bromoacetyl)methanesulfonanilide (4) (Method
A). Bromine (15.0 g, 94 mmol) was added dropwise over
5 min to a solution of 4′-acetylmethanesulfonanilide (2) (20
g, 94 mmol) in glacial acetic acid (400 mL) with stirring at
55 °C. After completion of the addition, the resulting
mixture was further stirred at the same temperature for 10
min and became colorless. Removal of acetic acid and
trituration with 2-propanol (200 mL) afforded 4′-(2-bro-
moacetyl)methanesulfonanilide (4) (25.12 g, 92% yield) as
1
yellowish solid: mp 155-156 °C; H NMR (200 MHz,
DMSO-d6) δ 2.55 (s, 3H), 3.15 (s, 3H), 7.29 (dd, 2H, J )
6.9, 2.6 Hz), 7.94 (dd, 2H, J ) 6.8, 1.9 Hz), 10.4 (br s, 1H);
IR (Nujol) 1670, 1600 cm-1; MS (EI) m/z 214 (M+). Anal.
Calcd for C9H11NO3S: C, 50.69; H, 5.20; N, 6.57. Found:
C, 50.31; H, 5.01; N, 6.52.
Large-Scale Preparation of 4′-Acetyl-2′-bromomethane-
sulfonanilide (3) (Method B). Bromine (59.0 kg, 370 mol)
was added dropwise over 1 h to a solution of 4′-acetyl-
methanesulfonanilide (2) (39.4 kg, 185 mol) in glacial acetic
acid (788 L) and water (263 L) with stirring at 15 °C. After
completion of the addition, the resulting mixture was further
stirred at the same temperature for 6 h, was treated with
sodium bisulfite (23.1 kg, 222 mol) in water (115 L), and
then was concentrated under reduced pressure to ∼120 L.
To the residue was added water (400 L), and stirring was
continued at 5 °C overnight. The precipitate was filtered
off and washed with water (160 L). Drying under reduced
pressure afforded 4′-acetyl-2′-bromomethanesulfonanilide (3)
(52.5 kg, 97% yield) as a white solid: mp 123-125 °C; 1H
NMR (200 MHz, DMSO-d6) δ 2.58 (s, 3H), 3.17 (s, 3H),
7.60 (d, 1H, J ) 8.5 Hz), 7.95 (dd, 1H, J ) 8.5, 2.0 Hz),
8.18 (d, 1H, J ) 2.0 Hz), 9.60 (br s, 1H); IR (Nujol) 1690,
1600 cm-1; MS (EI) m/z 292 (M+), 294 (M+ + 2). Anal.
Calcd for C9H10BrNO3S: C, 37.00; H, 3.45; N, 4.79.
Found: C, 36.82; H, 3.25; N, 4.71.
X-ray Crystallographic Analysis12 of 3. Colorless
prismatic crystals of 3 (C9H10BrNO3S) were grown from
acetone-isopropyl ether solution. Diffraction measurements
were performed on a Rigaku AFC-5R diffractometer using
graphite-monochromatized Cu KR radiation (λ ) 1.541 78
Å). Crystal data: C9H10BrNO3S, Mr ) 292.15, triclinic, a
) 8.969(7) Å, b ) 11.00(3) Å, c ) 5.590(5) Å, â )
94.96(7)°, V ) 543(1) Å3, Z ) 2, Dcalc ) 1.786 g/cm3, µ )
68.78 cm-1, F(000) ) 292.00, T ) 297 K. A total of 1890
reflections were collected using the ω-2θ scan technique
within a 2θ range of 125.7°. The structure was solved by
heavy-atom Patterson methods and refined by a full-matrix
least-squares method using 1852 reflections (I > 1.50σ(I)).
1
a white solid: mp 167-168 °C dec; H NMR (200 MHz,
DMSO-d6) δ 3.14 (s, 3H), 4.85 (s, 2H), 7.30 (d, 2H, J )
8.7 Hz), 7.99 (d, 2H, J ) 8.7 Hz), 10.46 (br s, 1H); IR
(Nujol) 1695, 1670, 1610, 1595, 1520 cm-1; MS (EI) m/z
292 (M+), 294 (M+ + 2). Anal. Calcd for C9H10BrNO3S:
C, 37.00; H, 3.45; N, 4.79. Found: C, 37.14; H, 3.31; N,
4.70.
4′-Acetyl-2′,6′-dibromomethanesulfonanilide (5) (Method
C). 4′-Acetyl-2′,6′-dibromomethanesulfonanilide (5) was
prepared by the reaction of 4′-acetyl-2′-bromomethanesulfo-
nanilide (3) (2.0 g, 6.8 mmol) and sodium acetate (2.81 g,
34.3 mmol) with excess bromine (2.18 g, 13.6 mmol) in
acetic acid-water at a higher temperature (60 °C). After
completion of the reaction (monitored by TLC), the reaction
mixture was cooled to 5 °C. The precipitate was filtered
off, washed with water and 2-propanol, and dried in Vacuo
to afford pure 4′-acetyl-2′,6′-dibromomethanesulfonanilide
(5) as a white solid in 57% yield: mp 164-166 °C; 1H NMR
(200 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.61 (s, 3H), 8.19 (s,
2H), 9.85 (br s, 1H); IR (Nujol) 1685, 1590, 1610, 1550
cm-1; MS (EI) m/z 370 (M+), 372 (M+ + 2), 374 (M+ +
4). Anal. Calcd for C9H9Br2NO3S: C, 29.13; H, 2.44; N,
3.77. Found: C, 28.85; H, 2.25; N, 3.65.
4′-(2-Bromoacetyl)-2′-bromomethanesulfonanilide (6).
4′-(2-Bromoacetyl)-2′-bromomethanesulfonanilide (6) was
prepared from 4′-acetyl-2′-bromomethanesulfonanilide (3)
(100%, method A): mp 142-145 °C; 1H NMR (200 MHz,
DMSO-d6) δ 3.22 (s, 3H), 4.94 (s, 2H), 7.61 (d, 1H, J )
5.2 Hz), 8.00 (dd, 1H, J ) 6.0, 2.2 Hz), 7.26 (d, 1H, J )
2.0 Hz), 9.65 (br s, 1H); IR (Nujol) 1680, 1600, 1560, 1500
cm-1; MS (EI) m/z 370 (M+), 372 (M+ + 2), 374 (M+ +
76
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Vol. 2, No. 2, 1998 / Organic Process Research & Development